resence and absence of 9 cis RA, showing again the important role of the NF B pathway in the protec tion of 9 cis RA against apoptosis. These data strongly support that this protection is mediated by NF B dependent mechanisms. Discussion A comple and intricate network things of signaling pathways determines whether a cell will either proliferate, differ entiate, survive or die. Retinoids, due to their strong dif ferentiative potential, have been widely used for both cancer therapy and cancer prevention. There are many e amples in the literature of distinct cell types whose differentiation is under the control of retinoids embryonal carcinoma cells, promyelocytic leukemia cells, neuroblastoma cells, normal erythroid progenitors, etc.

In addition to differentiation induction, retinoids are able to initiate several other programs that may contribute to its therapeutical potential. Indeed, it has been shown that retinoids induce apoptosis of APL cells and blasts of APL patients through selective para crine action of the death ligand TRAIL. In breast cancer cells, we provide evidence that retinoic acid induces cell growth inhibition and depending on cell conte t, promotes a sort of differentiation without affecting viability or makes the cells enter a fully apopto tic program. The finding that 9 cis RA causes differen tiation of T47D cells is in agreement with the previously reported accumulation of lipid droplets in cytoplasmic vesicles and milk protein casein in normal mammary epithelial cells, and in the breast cancer cell lines MCF7 and AU565 treated with retinoids.

However, further studies are needed to determine whether the differentiation characterized by accumula tion of cellular lipid depots contributes to the antiproli ferative effects of retinoic acid in breast cancer cells. A circuitry of several apoptotic programs is induced in breast cancer cells by retinoic acid. We have previously provided evidence that retinoids promote the induction of TRAIL not only in hematopoietic but also in breast cancer cells. In the current study, we have shown that induction of TRAIL and FAS by retinoic acid in the breast cancer cell line H3396 correlates with an increase in the number of apoptotic cells. In accordance with studies that report that TRAIL and FAS signal through caspase 8 activation, the activity of this enzyme is induced in H3396 cells treated with 9 cis RA or with e ogenous TRAIL.

Although additional studies will be required to clarify the possible involvement of the e trinsic death pathway in retinoic induced apoptosis in H3396 cells, activation of downstream caspases like cas pase 9, as well as the release Drug_discovery of cytochrome c and SMAC DIABLO from the mitochondria to the cytosol and the loss of the mitochondrial inhibitor Rucaparib membrane potential prove that the intrinsic pathway is dominantly involved in retinoic acid induced apoptosis. Parado ically in certain breast cancer cells, retinoic acid induces concomitantly to TRAIL upregulation, the activation of a gene pro